Clin Infect Dis. 2011 Phyo 977 84

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M A J O R A R T I C L E

Dihydroartemisinin-Piperaquine Versus

Chloroquine in the Treatment of Plasmodiumvivax Malaria in Thailand: A RandomizedControlled Trial

Aung Pyae Phyo,1 Khin Maung Lwin,1 Ric N. Price,4,5 Elizabeth A. Ashley,1,2,5 Bruce Russell,6 Kanlaya Sriprawat,1

Niklas Lindegardh,2,5 Pratap Singhasivanon,3 Nicholas J. White,2,3 and Francxois Nosten1,2,3

1Shoklo Malaria Research Unit, Mae Sod, 2Mahidol Oxford Research Unit, and 3Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand;4Global Health Division, Menzies School of Health Research, Charles Darwin University, Australia; 5Centre for Tropical Medicine, Nuffield Department

of Clinical Medicine, University of Oxford, United Kingdom; and 6Laboratory of Malaria Immunobiology, Singapore Immunology Network, Biopolis,

Agency for Science Technology and Research (A*STAR)

Background. Chloroquine (CQ) remains the treatment of choice for Plasmodium vivax malaria. Initiallyconfined to parts of Indonesia and Papua, resistance of P. vivax to CQ seems to be spreading, and alternative

treatments are required.

Methods. We conducted a randomized controlled study to compare the efficacy and the tolerability of CQ and

dihydroartemisinin-piperaquine (DP) in 500 adults and children with acute vivax malaria on the Northwestern

border of Thailand.

Results. Both drugs were well tolerated. Fever and parasite clearance times were slower in the CQ than in the DP

group (P, .001). By day 28, recurrent infections had emerged in 18 of 207 CQ recipients compared with 5 of 230

treated with DP (relative risk, 4.0; 95% confidence interval [CI], 1.5110.58; P5 .0046). The cumulative risk of

recurrence with P. vivaxat 9 weeks was 79.1% (95% CI, 73.5%84.8%) in patients treated with CQ compared with

54.9% (95% CI, 48.2%61.6%) in those receiving DP (hazard ratio [HR], 2.27; 95% CI, 1.82.9; P, .001). Children

,5 years old were at greater risk of recurrent P. vivax infection (74.4%; 95% CI, 63.2%85.6%) than older patients

(55.3% [95% CI, 50.2%60.4%]; HR, 1.58 [95% CI, 1.12.2]; P5 .005). In vitro susceptibility testing showed that

13% of the tested isolates had a CQ median inhibitory concentration .100 nmol/L, suggesting reduced susceptibility.

Conclusions. The efficacy of CQ in the treatment of P. vivax infections is declining on the Thai-Myanmar

border. DP is an effective alternative treatment.

Clinical Trials Registration. ISRCTN87827353.

Chloroquine (CQ) remains the drug of choice for

the prevention and treatment of infections caused by

Plasmodium vivax in most endemic regions, although

the decline in the efficacy of CQ may have been over-

looked [1, 2]. CQ-resistant P. vivaxwas first described

in 1989 in Papua New Guinea [3]. For several years,

reports of reduced CQ efficacy were limited to the

island of New Guinea [46]. The degree of CQ re-

sistance in Papua, Indonesia and Papua New Guineahas now become so severe that local antimalarial

treatment policies have been revised to adopt arte-

misinin combination therapy for both Plasmodium

falciparum and P. vivax infections. More recently,

CQ-resistant P. vivax has been documented across

the Indonesian archipelago [1] and in Myanmar [7, 8],

South Korea [9], Turkey [10], the Horn of Africa [11],

and South America [12].

Received 22 April 2011; accepted 16 August 2011.

Correspondence: Francxois Nosten, MD, Shoklo Malaria Research Unit, Mahidol

Oxford University Tropical Medicine Research Unit, 68/30 Baan Tung Rd, PO Box

46, Mae Sod, Tak Province 63110, Thailand ([email protected]).

Clinical Infectious Diseases 2011;53(10):977984

The Author 2011. Published by Oxford University Press on behalf of the Infectious

Diseases Society of America. All rights reserved. For Permissions, please email:

[email protected].

This is an Open Access article distributed under the terms of the Creative Commons

Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/

2.5/), which permits unrestricted non-commercial use, distribution, and reproduction

in any medium, provided the original work is properly cited.

1058-4838/2011/5310-0002$14.00

DOI: 10.1093/cid/cir631

Treatment of Plasmodium vivaxWith Dihydroartemisinin-Piperaquine d CID 2011:53 (15 November) d 977


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In Thailand, malaria remains a problem along the borders

with Cambodia and Myanmar, where multidrug-resistant

P. falciparum is endemic. In 1996, in camps for displaced per-

sons of the Karen ethnic minority on the Northwestern border

of Thailand, we found that CQ was a highly effective treatment

for P. vivax malaria, with ,3% of patients having a recurrence

(relapse, reinfection or recrudescence) by day 28 [13]. However,

in a study conducted 7 years later in neighboring Myanmar,

almost 35% of treated patients had a parasite recurrence by day28, raising the possibility that resistance was spreading along the

Thai-Myanmar border [7]. In addition, in vitro sensitivity

testing on fresh parasite isolates collected between 2003 and

2007 in the same region indicated a decreased susceptibility to

CQ in some isolates [14]. Patients with CQ-resistant P. vivaxcan

be treated effectively with the dihydroartemisinin-piperaquine

combination (DP) as well as other artemisinin combination

therapies [2, 5, 15]. To reassess the efficacy of CQ in the treatment

of P. vivax infections on the Northwestern border of Thailand

and study the efficacy of DP, we conducted a randomized

controlled trial in patients with P. vivax monoinfections.

METHODS

Patients

The study took place in the Shoklo Malaria Research Unit clinics

on the Thailand-Myanmar border, an area of low (entomologic

inoculation rate, ,1) and seasonal malaria transmission[16].

Patients .1 year old and with a body weight of$5 kg were

eligible for enrollment if they had a microscopically confirmed

monoinfection of P. vivax (parasitemia, $5/500 white blood

cells), if they were febrile (axillary temperature,$37.5C) or hada history of fever, and if they or their guardians gave fully in-

formed consent. Patients were excluded if they had a known

hypersensitivity to the study drugs; had intercurrent illness or

were pregnant, lactating, or severely anemic (hematocrit,

,20%); or had received mefloquine treatment in the previous

60 days or DP in the previous 3 months.

Randomization

Patients were allocated to the treatment arms based on a pre-

generated randomization list in blocks of 20. The individual

allocations were concealed in sealed envelopes and opened onlyafter enrollment by the field team. Although patients and clinic

workers were not blinded to the treatment arm after allocation,

laboratory technicians were unaware of treatment allocation.

Drugs

Chloroquine (Government Pharmaceutical Organization,

Thailand) was given once a day for 3 days, with a target dose of

25 mg base/kg with a glass of water. DP (Duocotexin; Holley

Peoples Republic of China) was administered once a day for

3 days with milk, with a total target dose of 7 mg/kg for dihy-

droartemisinin and 55 mg/kg for piperaquine. All patients with

a normal G6PD test result were offered a course of 14 days of

primaquine (0.5 mg base/kg/d) at the end of the follow-up

period. This delay was instituted because primaquine itself is

active against asexual stages of P. vivax [17] and its adminis-

tration earlier would have compromised the analysis of the

efficacy of CQ and DP.

Enrollment Procedures

A case-record form was completed for all patients documenting

symptoms before clinic attendance, concomitant illness, drug

history and physical examination. Capillary blood was collected

formalaria thick andthin films, hematocrit, and G6PD deficiency

testing. Patients .1 year of age presenting with parasitemia of

.100 P. vivaxtrophozoites/500 white blood cells were asked to

provide 5 mL of venous blood for in vitro sensitivity testing.

Follow-up

Patients were seen daily from admission until they were afebrile

and aparasitemic and then weekly until day 63. At each visit,

temperature was measured and a symptom questionnaire was

completed. Capillary blood was taken for malaria blood smear

and hematocrit weekly. Any concomitant medication taken

during the study period was recorded. Patients presenting to the

clinic within the follow-up period with microscopically con-

firmed P. vivax had capillary blood sampling for measurement

of CQ and desethylchloroquine plasma concentrations. Patients

with P. falciparum infection diagnosed during the follow-up

period were withdrawn from the study and treated with the

standard 3-day treatment of mefloquine and artesunate.

Drug Measurements

CQ and desethylchloroquine plasma concentrations were mea-

sured in patients .10 years old at the time of recurrent malaria.

Plasma drug concentrations were quantified using solid-phase

extraction and high-performance liquid chromatography with UV

detection [18]. The limit of detection was 1 ng/mL for both drugs.

Laboratory Methods

Malaria blood films were stained with Giemsa, and parasite

counts were expressed as the number of parasites per 1000 red

blood cells or, if the parasitemia was ,1% packed red blood

cells, as the number of parasites per 500 white blood cells. G6PDdeficiency was assessed by the fluorescent spot test SQMMR500

(R&D Diagnostic). In vitro samples for drug susceptibility were

processed and analyzed as described elsewhere [14].

Study End Points

The analysis of efficacy was conducted using a modified

intention-to-treat analysis that included all patients who fulfilled

the enrollment criteria. The primary end point was the overall

risk of recurrence with P. vivax during the 63-day follow-up

978 d CID 2011:53 (15 November) d Phyo et al


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period. Secondary end points included the risk of reappearance

ofP. falciparum, the parasite and fever clearance times, and the

adverse events reported by the patients.

Sample Size

The original sample size of 500 patients had 80% power and

95% confidence to detect a 15% difference in the primary end

point, assuming a 50% recurrence rate in the CQ group,

allowing for up to 15% loss to follow-up by day 63.

Statistical Analysis

Data were double entered into Microsoft Access software and

analysis was performed using SPSS for Windows (version 16;

SPSS). The MannWhitney U test was used for nonparametric

comparisons, and Student ttest or 1-way analysis of variance for

parametric comparisons. Proportions were examined using v2

with Yates correction or by Fishers exact test. Efficacy end

points were assessed by survival analysis, in which the cumulative

risk of failure was calculated by the KaplanMeier product limit

formula and compared by the MantelHaenszel log-rank test. In

addition, treatments were compared and the hazard ratio (HR)

calculated using a Cox proportional hazards model. Data were

censored for patients who were unavailable for follow-up or, in

the case of secondary end points, presented again with a different

outcome and not regarded as treatment failures. Those patients

with recurrent vomiting or adverse drug effects, which required

early termination of treatment and the administration of rescue

therapy, were regarded as therapeutic failures.

Ethical Approval

The study was approved by the Ethics Committee of the Faculty

of Tropical Medicine, Mahidol University (MUTM 2006-029),

and the Oxford Tropical Research Ethics Committee, Oxford

University (OXTREC 027-05). The trial was registered at

ClinicalTrials.gov (ISRCTN87827353).

RESULTS

Recruitment and Baseline Characteristics

Between January 2007 and December 2008, 500 patients were

enrolled in the study. Eight of these patients did not meet the

inclusion criteria and were excluded from further analysis

(Figure 1). The baseline characteristics of the 492 patients in the

evaluable population (modified intention-to-treat analysis) are

presented in Table 1; there were no differences in baseline

characteristics between treatment arms. Follow-up to day 63 or

day of failure (per-protocol analysis) was achieved in 86.7% of

Figure 1. Study profile.



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patients (215/248) treated with DP and 87.3% (213/244) given

CQ (P5 .95). Nonadherence to follow-up was more likely in

adults (16%; 47/291) than in children (8.5%; 17/201; P5 .01),

but these patients otherwise had similar baseline characteristics

as those who were adherent to follow-up. With the exception of

a 3-year old boy who vomited CQ repeatedly, there were no

other early treatment failures. In patients receiving a complete

course of treatment, the median dose of CQ administered in the

CQ arm was 24.8 mg base/kg (range, 21.329.4), and patients in

the DP arm received median doses of 6.7 mg/kg (range, 510)

of dihydroartemisinin and 53.3 mg/kg (range, 4080) of

piperaquine.

Early Therapeutic Response

Within 24 hours after the start of treatment, 63.7% of patients

(156/245) receiving DP had clearance of asexual parasitemia

after, compared with only 21.1% (51/242) receiving CQ (odds

ratio, 6.6; 95% confidence interval [CI], 4.310.0; P, .001).

After 48 hours, these proportions had risen to 97.5% (237/243)

and 84.1% (201/239), respectively (P , .001). Five patients

treated with CQ were still parasitemic at 72 hours, and all but

1 had cleared by 96 hours. In the CQ but not in the DP group,

patients with schizont stages present at enrollment were more

likely to be parasitemic at 24 hours than were patients with

only trophozoite asexual stages present (93% [69/74] vs 72.6%

[122/168], respectively; odds ratio, 5.2; 95% CI, 1.915.7;

Table 1. Patient Characteristics at Baselinea

Characteristic DP treatment (n 5 248) CQ treatment (n 5 244)

Asexual parasitemia, geometric mean (95% CI), lL21 3776 (31114582) 4406 (36375339)

Gametocytemia, geometric mean (95% CI), lL21 214 (178257) 280 (236333)

Gametocytemia present 85 (210) 84 (205)

Schizonts present at enrollment 32 (79) 30 (74)

Male sex 70 (173) 64 (155)

G6PD deficiency 6.1 (15/247) 5.3 (13)

Weight, median (range), kg 45 (774) 45 (961)

Age, median (range), years 18 (157) 18 (163)

Age, years

,5 14 (34) 12 (30)

514 27 (67) 29 (70)

.14 59 (147) 59 (144)

Fever .38.0C 42 (94/225) 42 (97/229)

Duration of febrile illness, median (range), days 2 (08) 2 (05)

Hematocrit, mean (SD), % 37.2 (5.0) 37.6 (5.2)

Anemia (hematocrit ,30%) 4.5 (11/247) 5.8 (14/242)

Splenomegaly 14 (34/243) 12 (29/237)

Hepatomegaly 23 (57/247) 26 (63)

Abbreviations: CI, confidence interval; CQ, chloroquine; DP, dihydroartemisinin-piperaquine; SD, standard deviation.a

Unless otherwise indicated, data represent % (No.) of patients, with denominators where these were smaller than the full sample.

Table 2. Risk of Treatment Failure: Modified Intention-to-Treat Analysis

Cumulative risk of recurrencea (95% CI), %

Type of recurrence DP treatment (n 5 248) CQ treatment (n 5 244) Hazard ratiob (95% CI)

Plasmodium vivax

Day 63c 54.9 (48.261.6) 79.1 (73.484.8) 2.27 (1.82.9) (P, .001)

Day 28d 4.1 (1.66.6) 9.8 (5.913.7) 2.3 (1.14.9) (P5 .032)

Plasmodium falciparum

Day 63d 8.0 (4.511.5) 11.5 (6.616.4) 1.5 (0.82.9) (P5 .176)

Day 28d 2.4 (0.44.4) 7.8 (4.311.3) 3.1 (1.27.9) (P5. 015)

Abbreviations: CI, confidence interval; CQ, chloroquine; DP, dihydroartemisinin-piperaquine.a

Cumulative risk calculated by Kaplan-Meier method. Patients with an incomplete course of treatment were included in the analysis conservatively as treatment

failures; other patients with incomplete follow-up were censored on the last day of follow-up as nonfailures.b

Hazard ratios were calculated using a Cox proportional hazards model.c

Primary end point.d

Secondary end point.



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P5 .0005). Overall 84.3% of patients (415/492) had P. vivax

gametocytemia evident on their admission blood film. By

48 hours, this proportion had fallen to 7.6% (18/238) in the CQ

group and 1.3% (3/239) in the DP group (P5 .001). Although

all patients had a history of fever (median duration, 2 days) on

admission to the study, only 42.1% (191/454) were febrile at

enrollment. Fever clearance was significantly faster in patients

receiving DP; 92.9% (183/197) were afebrile by day 2 compared

with 82.2% (171/208) of those receiving CQ (P5 .001).

Efficacy Analysis

In the modified intention-to-treat analysis, the cumulative risk

of recurrence with P. vivax at 9 weeks was 79.1% (95% CI,

73.5%84.8%) in patients treated with CQ compared with

54.9% (95% CI, 48.2%61.6%) in those receiving DP (HR, 2.27;

95% CI, 1.82.9; P, .001) (Table 2). This significant difference

had already emerged by day 28 of follow-up and was confirmedat both day 28 and day 63 in the per-protocol population (Table 3

and Figure 2). By day 28, recurrent infections had emerged in

8.7% CQ recipients (18/207) compared with 2.2% (5/230)

treated with DP (relative risk, 4.0; 95% CI, 1.5110.58; P5 .005).

The median time to recurrence ofP. vivaxinfection was 56 days

(interquartile range [IQR], 4256; range, 1465) in the DP

group compared with 42 days (IQR, 3549; range 1966) in the

CQ group (P , .001). Falciparum malaria was also more

A

B

Figure 2. A, Cumulative risk of treatment failure in patients with Plasmodium vivax parasitemia (P. vivax alone or mixed infections). Diamondsrepresent chloroquine (CQ); circles, dihydroartemisinin-piperaquine (DP). The overall difference between treatment groups at day 63 was significant

(P, .001). B, Cumulative risk of treatment failure in patients with Plasmodium falciparumparasitemia (P. falciparuminfection alone or mixed infections).

The overall difference between treatment groups was significant at day 28 ( P5 .015) but not by day 63 (P5 .176).



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common in the CQ group; by day 28, 1 patient in the DP group

and 15 in the CQ group were parasitemic with P. falciparum

(either alone or mixed with P. vivax) (HR, 3.1; 95% CI, 1.27.9;

P5 .015). These figures had increased to 13 and 21, respectively,

by day 63, although this difference was no longer significant in

the modified intention-to-treat analysis (Table 2). Recurrent

malaria within 28 days (both P. vivax and P. falciparum) was

therefore 6.11 (95% CI, 2.6114.29) times more frequent in CQ

recipients than in DP recipients.

Cox regression analysis (modified intention-to-treat pop-

ulation) revealed 2 independent baseline factors predicting

recurrent P. vivaxinfection: treatment with CQ (adjusted HR

[AHR], 2.3; 95% CI, 1.82.9; P , .001) and young age

(14 years) (AHR, 1.58; 95% CI, 1.12.2; P5 .005 for com-

parison with older children and adults). In addition, patients

treated with CQ who had delayed parasite clearance (still

parasitemic on day 2), were at significantly greater risk

of recurrent P. vivax infection by day 28 (23.5%; 95% CI,

9.2%37.8%) compared with 6.5% (95% CI, 2.4%10.6%) in

patients whose initial parasitemia had cleared within 48 hours

(P5 .004). This difference remained significant after age andbaseline parasitemia were controlled for (AHR, 4.2; 95% CI,

1.611.1; P5 .004).

The minimum effective plasma concentration (MEC) of

combined CQ plus desethylchloroquine considered effective

against CQ-susceptible parasites is 12 ng/mL [1, 19]. Of 156

recurrences of P. vivax infection in the CQ group, plasma

concentrations of CQ and desethylchloroquine were de-

termined in 85 patients (54%). In the 5 patients with

recurrence before day 28, these plasma concentrations at the

time of failure were 4.59, 5.00, 5.00, 7.50, and 15.5 ng/mL. The

patient with a plasma CQ-desethylchloroquine concentration

of 15.5 ng/mL (higher than the MEC of 12 ng/mL) had

treatment failure at day 21.

Symptoms and Tolerability

Early vomiting within the first hour of drug administration was

recorded in 7.9% of patients treated with DP (19/241) and 7.1%

of those treated with CQ (17/241) (P5 .86). With the exception

of the 3-year-old boy in the CQ group, all patients tolerated drug

readministration (Figure 3). The only significant difference be-

tween the 2 treatment arms in the development of symptoms

was a 4.0-fold (95% CI, 1.511.3-fold) increased risk of vomiting

on days 1 and 2 associated with CQ; 10.5% of patients receiving

CQ (22/209) vomited, compared with 2.8% (6/211) of those

receiving DP (P5 .003). The risk of diarrhea was 0.2% in both

treatment arms assessed at day 7. No serious adverse event

occurred during the study.

Parasite In Vitro Drug SusceptibilityCQ susceptibility was assessed in 50 isolates before administra-

tion of antimalarial medication, of which 43 had a majority of

ring stages present. Drug susceptibility could be assessed suc-

cessfully in 86% of these isolates (37/43). The median inhibitory

concentration (IC50) for CQ was 27.4 ng/mL (IQR, 11.846.1l;

range, 3.4124.8) and 51.7 ng/mL (IQR, 45.369.3; range, 12.5

121.7) for piperaquine (Figure 4). In total, 13.5% of isolates

(5/37) had CQ IC50 values .50 ng/mL (100 nmol/L).

Figure 3. Adverse events on day 1 or 2 in patients without symptoms at admission.



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DISCUSSION

An estimated 2849 million persons are at risk ofP. vivaxinfection

[20], with between 76 and 391 million clinical cases per year. The

efficacy of CQ, the drug used to treat vivax malaria for.50 years,

has fallen in some areas, and resistance seems to be spreading. The

assessment of treatment efficacy in P. vivaxis more difficult than

in P. falciparum, because there are no genotyping methods that

reliably distinguish relapses from new infections, and long-term

cultures of P. vivax cannot be maintained, thereby confining in

vitro testing of drugs to assays on fresh isolates. This means that it

is difficult to document unequivocal cases of treatment failure in

areas where resistance is emerging, but anyP. vivaxinfection that

occurs within 28 days after the start of CQ treatment, whether

recrudescence, relapse, or new infection, has grown through re-

sidual CQ concentrations in blood. If these concentrations are

adequate, then the infection is resistant, by definition [21].

In this study we assessed the in vivo efficacy of CQ and

compared it with that of DP, an artemisinin combination

therapy with documented efficacy against CQ-resistant P. vivax

[5, 22, 23]. More than 8% of patients treated with CQ had

a recurrent infection within 28 days, and this rate rose to 22% in

young children. Parasite and fever clearance times were both

significantly faster after DP treatment. The artemisinin de-

rivatives are the most rapidly acting drugs against P. vivax[17],

so this difference is expected. The artemisinin component of DP

contributes significantly to the initial therapeutic response but

would not be expected to affect subsequent relapses or re-infections. Parasite clearance time was prolonged after CQ

treatment, with 16% of patients still parasitemic at 48 hours and

2% at 76 hours. Delayed parasite clearance, as defined by par-

asitemia on day 2, increased the subsequent risk of recurrent

P. vivax infection within 28 days by almost 4-fold after CQ

treatment. Interestingly, patients who had schizonts in the

peripheral blood on admission had significantly slower parasite

clearance after CQ treatment. This presumably reflects

uninterrupted schizogony and is consistent with in vitro ob-

servations showing marked reduction in activity of CQ against

these stages [24]. As expected, children who have less naturalimmunity against malaria were more at risk of parasite re-

currence independent of the above-mentioned risk factors.

During follow-up, the risk of recurrence ofP. vivaxinfection was

significantly greater after CQ than after DP treatment

(AHR, 2.3), a difference that was already apparent by day 28.

Recurrences can result from recrudescence, reinfection, or

relapses from dormant liver stages, although we were unable to

distinguish between these. Both CQ and DP have long elimi-

nation phases and therefore persistent blood concentrations,

delaying the time to the first relapse. In areas where CQ sensitive

parasites predominate, the prolonged posttreatment prophylaxis

of CQ usually affords a minimum of 28 days without recurrence.

In the current study the main difference in the parasitologic

response between CQ and DP was evident within this period,

with nearly 9% of patients treated with CQ having a recurrence

by day 28. This figure is 3 times higher than in our previous

study in 1996, but one-third of that reported from neighboring

Myanmar [7]. In addition, in 1 of these early recurrences

Figure 4. Ex vivo drug susceptibility to chloroquine and piperaquine.IC50, median inhibitory concentration.

Table 3. Risk of Treatment Failure: Per-Protocol Analysis

Patients with recurrence, % (no.)

Recurrence DP treatment CQ treatment Odds ratio (95% CI)Plasmodium vivax

Day 63a 55.1 (113/205) 80.3 (155/193) 3.3 (2.15.3) (P, .001)

Day 28a 2.2 (5/230) 8.7 (18/207) 4.3 (1.513.5) (P5 .005)

Plasmodium falciparum

Day 63b 10.1 (13/129) 29.6 (21/71) 3.8 (1.68.7) (P, .001)

Day 28b 0.4 (1/228) 7.0 (15/215) 17.0 (2.3349) (P, .001)

Abbreviations: CI, confidence interval; CQ, chloroquine; DP, dihydroartemisinin-piperaquine.a

Excludes all patients with protocol violations or incomplete follow-up due to P. falciparum parasitemia before day 61 (for day 63 risk) or 26 (for day 28 risk).b

Excludes all patients with protocol violations or incomplete follow-up due to recurrent P. vivax parasitemia before day 61 (for day 63 risk) or 26 (for day 28 risk).



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(day 21) the combined CQ plus desethylchloroquine plasma

concentration (15.5 ng/mL) was higher than the MEC of 12 ng/

mL, demonstrating recurrence through drug levels that would

be expected to inhibit CQ-sensitive parasites [1, 19]. In the latest

published study in the same area, primaquine was administered

with CQ, which may have masked the emergence of recurrences

by day 28 [25]. In the present study, the confounding effect of

primaquine asexual stage activity was avoided by adminis-

tering the drug at the end of the follow-up period, to focussolely on evaluating the main schizontocidal drugs. Associated

in vitro results highlight the fact that whereas the IC50 values

for CQ were generally low (median, 27.4 ng/mL), some iso-

lates exhibited relatively high values. Drug susceptibility

testing was performed only in a small proportion of patients,

and hence our study was underpowered to assess the in vivo

ex vivo correlates. However, in the parasites that could be

tested, 13% of isolates had reduced susceptibility to CQ

(IC50 .100 nmol/L), in keeping with the overall 9% risk of

recurrence within 28 days.

In conclusion our results suggest that CQ efficacy on theNorthwestern border of Thailand is declining. DP is a suitable

alternative in the treatment of P. vivax infections in this area,

although further studies are needed to define how best to combine

this treatment with appropriate antirelapse therapy (primaquine).

Notes

Acknowledgments. We thank all the patients and staff at all the Shoklo

Malaria Research Unit (SMRU) clinics who participated in this study.

Financial support. Holley Pharm provided financial support for the

study and donated the dihydroartemisinin-piperaquine but had no role in

the planning, design, and conduct of the study, nor in the analysis and

interpretation of results or writing of the manuscript. The SMRU is attached tothe Faculty of Tropical Medicine, Mahidol University. This investigation was

part of the Wellcome Trust Mahidol University Oxford Tropical Medicine

Research Programme, supported by the Wellcome Trust of Great Britain.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the

content of the manuscript have been disclosed.

Author contributions. A. P. P., K. M. L., E. A., and F. N. conducted the

trial; R. P. analyzed the data; B. R. and K. S., performed the in vitro tests;

N. L. measured the drug concentrations; P. S., E. A., N. J. W., and F. N.

conceived the protocol and supervised the study; all authors contributed to

the interpretation of data and writing of the manuscript.

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